Calpain is a cytosolic calcium-dependent cysteine protease. It is found in all mammalian tissue and cell types. The calpain family of proteases consists of two recognized proteins.
The first member of the calpain family is calpain I or μ-calpain which is the high sensitivity form and is activated by a low calcium concentration (2-75 μM). Calpain I is concentrated in synapses and neuronal cell bodies.
The second member of the calpain family is calpain II or m-calpain. It has a ribbon like structure and is the lower sensitivity form. It is activated by higher concentrations of calcium (200-800 μM). Calpain II is the dominant form.
Calpastatin is a known endogenous inhibitor of calpain I and calpain II. It has four internally repeated domains, each of which independently binds a calpain molecule in its active, Ca++-bound conformation with high affinity.
Calpains play an important role in various physiological processes. These processes include, inter alia, the cleavage of regulatory proteins such as protein kinase C (PKC) and degradation of cytoskeletal or microtubule-associated proteins (MAP) such as tau. Research has demonstrated that calpain inhibitors have improved recovery from the memory performance deficits and neuromotor disturbances. Calpain inhibitors inhibit the release of the 13-AP4 protein. Therefore, it has been suggested that they have a potential use as therapeutic agents in Alzheimer's disease. Calpain inhibitors have also had a protective effect on hypoxia-damaged kidneys and have had favorable effects following cardiac damage produced by ischemias of the heart (e.g., myocardial infarction) or reperfusion. It has also been found that calpain inhibitors have cytotoxic effects on tumor cells. Elevated calpain levels are also implicated in the pathophysiology of cerebral ischemia, platelet activation, NF-KB activation, muscular dystrophy, cataract progression and rheumatoid arthritis. with various pathophysiological processes such as, inflammations, muscular dystrophies, cataracts of the eyes, and injuries to the central nervous system (e.g., trauma).
Calpains reside in the cytosol of cells and are activated by Ca++ at a physiological pH. Its proteolytic activity appears to be selective against certain target proteins, such as components of the cytoskeleton and calmodulin-dependent enzymes.
Excessive excitation by a neurotransmitter glutamate can lead to death of nerve cells (neurons) and neurodegeneration. It is believed that toxic effects of glutamate comes from overactivation of its target glutamate receptors (e.g., under ischemic conditions or stroke). This in turn produces an influx of calcium ion (Ca++) into the neurons. The rise of cellular Ca++ level triggers the activation of calpain I. Calpain I then goes on to degrade cytoskeletal protein such as spectrin, which is believed to disrupt normal cellular functions, and eventually leads to cell death.